On Huntington's Disease Awareness Day: How Humanized Models Drive Therapeutic Innovation

May 15 marks International Huntington's Disease Awareness Day — a date not only meant to raise public awareness for those affected but also to highlight the urgent need for breakthroughs in treating this devastating condition. Known as the “disease of dancing,” Huntington's causes patients to gradually lose control over their bodies through involuntary movements, as if pulled by invisible strings, step by step into the decline of motor skills and cognitive functions. Globally, 3 to 7 people per 100,000 are enduring this suffering, while effective medical solutions remain elusive.

Pathogenic Mechanism of Huntington's Disease

Huntingtin (HTT) is a disease-associated gene linked to Huntington's disease (HD). It is widely expressed across various tissues and organs throughout the body, including the central nervous system, and is essential for normal development. Near the 5’end of the HTT gene's coding region lies a polymorphic trinucleotide repeat sequence—cytosine-adenine-guanine (CAG)—which, during translation, encodes a polyglutamine (polyQ) tract.

Huntington's disease is a neurodegenerative disorder characterized by the loss of neurons in the striatum. It is caused by abnormal expression of the trinucleotide (CAG) repeat sequence in the HTT gene. When the number of CAG repeats exceeds 35, it leads to an abnormal expansion of the polyglutamine (polyQ) tract, resulting in the misfolding of HTT protein fragments. These misfolded proteins abnormally interact with numerous other proteins and accumulate in the cell nucleus and neuronal terminals, disrupting neurotransmission, intracellular protein transport, and mitochondrial function. Ultimately, this cascade leads to neuronal dysfunction and degeneration.

Drug Development for Huntington's Disease

In recent years, drug development for Huntington’s disease has focused on eliminating or functionally correcting the mutant huntingtin protein (mHTT). The main therapeutic strategies include gene-silencing approaches—such as Roche’s antisense oligonucleotide (ASO) drug Tominersen and Wave Life Sciences’RNAi therapy WVE-003—as well as small-molecule drugs like PTC518, which promotes mHTT degradation, and ANX005, which targets neuroinflammation. Cutting-edge efforts also explore gene editing technologies and stem cell transplantation.

Although Tominersen did not meet expectations in its Phase III clinical trial, it provided critical data for target validation. Current research efforts are shifting toward optimizing delivery systems—such as AAV vectors capable of crossing the blood-brain barrier—and exploring combination therapies that synergize protein clearance with anti-inflammatory mechanisms. With the application of novel technologies like base editing and the advancement of adaptive clinical trials, the field is steadily overcoming key challenges and moving toward more precise and targeted therapies for Huntington's disease.

hHTT Q150 Knock-In Model

However, optimizing and advancing these therapeutic strategies requires a deeper understanding of the pathological mechanisms of Huntington’s disease, along with the development of experimental models that accurately recapitulate the disease's characteristics.

To support this need, we have developed the hHTT Q150 knock-in model—FVB-hHTT Q150 KI mice (Product No.: I001019). Using gene editing technology, a mutant human HTT gene sequence carrying 150 CAG repeats is precisely knocked into the mouse genome.

According to published studies, this mouse model exhibits pathological features and functional impairments characteristic of Huntington’s disease, making it a valuable tool for drug discovery, efficacy screening, and safety evaluation in HD research.

1. Behavioral Test: Open Field Test

a. At 2 months of age:

• Total distance traveled
• Percentage of time spent in the central area

Figure 1. Locomotor activity (A–C) and percentage of time spent in the central area (D–F) during the open field test in wild-type (WT) mice and FVB-hHTT Q150 KI mice.

• Central area movement speed & Peripheral area movement speed

Figure 2. Central area movement speed (A–C) and peripheral area movement speed (D–F) in the open field test for wild-type (WT) mice and FVB-hHTT Q150 KI mice.

b. At 3 months of age:

• Total distance traveled
• Percentage of time spent in the central area

Figure 3. Total distance traveled (A–C) and percentage of time spent in the central area (D–F) during the open field test in wild-type (WT) mice and FVB-hHTT Q150 KI mice.

• Central area movement speed & Peripheral area movement speed

Figure 4. Central area movement speed (A–C) and peripheral area movement speed (D–F) during the open field test in wild-type (WT) mice and FVB-hHTT Q150 KI mice.

2. Behavioral Test: Rotarod Test (3 months of age)

Figure 5. Latency to fall in the rotarod test for wild-type (WT) mice and FVB-hHTT Q150 KI mice.

3. Grip Strength, Rotarod Test, and Open Field Test at 14 Months of Age

Figure 6. Grip strength, rotarod performance, and open field analysis of 14-month-old hHTT-Q150 KI mice.

Recommended Neurological and Neuromuscular Models

Leveraging our well-established animal model development platforms, we offer over 2,000 ready-to-use KO/CKO mouse models related to the nervous system, as well as more than 20 types of genetically engineered and drug-induced rodent models for neurological diseases. These models encompass a wide range of targeting strategies, including knockout, conditional knockout, point mutation, transgenic, and humanized models. In addition to our off-the-shelf offerings, we also provide customized model generation and collaborative development services tailored to specific research needs.

Explore Our Research-Ready Neurological Disease Models